ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA RELEASE AND LEUKOCYTE MARGINATION IN INDOMETHACIN-INDUCED GASTRIC INJURY IN RATS
ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA RELEASE AND LEUKOCYTE MARGINATION IN INDOMETHACIN-INDUCED GASTRIC INJURY IN RATS
复制标题
DOI：
10.1016/0016-5085(95)90065-9
复制
发表时间：
1995-02-01
期刊：
影响因子：
29.4
通讯作者：
MORELLI, A
中科院分区：
文献类型：
--
作者：
SANTUCCI, L;FIORUCCI, S;MORELLI, A
背景/目的：多项研究表明，中性粒细胞边集是非甾体抗炎药致胃粘膜损伤的早期和危重事件。肿瘤坏死因子是一种促炎细胞因子，通过上调中性粒细胞和血管内皮细胞上黏附分子的表达而导致中性粒细胞边集。本研究调查了调节肿瘤坏死因子合成和释放的物质是否影响中性粒细胞边集和消炎痛引起的胃损伤。方法：用不同剂量的吲哚美辛单独或与已知可增加或抑制肿瘤坏死因子(己酮可可碱、地塞米松、粒细胞集落刺激因子[G-CSF])合成和释放的物质(白介素2和脂多糖)联合作用。结果：吲哚美辛可引起剂量依赖性损伤，并使中性粒细胞边集和血浆肿瘤坏死因子浓度升高。白细胞介素2和脂多糖可显著增加肿瘤坏死因子的释放、中性粒细胞边集和胃粘膜损伤，但地塞米松、己酮可可碱和G-CSF的应用几乎可提供全部保护作用。单独应用G-CSF可显着增加胃中性粒细胞边集，但对消炎痛诱导的胃病有保护作用。结论：调节肿瘤坏死因子合成和释放的药物通过调节中性粒细胞边集而影响胃对吲哚美辛的敏感性。G-CSF增加了PMN的浸润，但对粘膜损伤有保护作用，提示仅有PMN的边集不足以引起粘膜损伤。
Background/Aims: Several studies have shown that polymorphonuclear neutrophil leukocyte (PMN) margination is an early and critical event in the pathogenesis of gastric mucosal injury caused by nonsteroidal anti-inflammatory drugs. Tumor necrosis factor (TNF) or is a proinflammatory cytokine that causes PMN margination by up-regulating expression of adhesion molecules on both PMN and endothelial cells. This study investigated whether substances that modulate TNF synthesis and release influence PMN margination and indomethacin-induced gastric damage. Methods: Rats were treated with several doses of indomethacin alone or in association with substances known to increase (interleukin 2 and lipopolysaccharide) or inhibit (pentoxifylline, dexamethasone, granulocyte colony-stimulating factor [G-CSF]) TNF synthesis and release. Results: Indomethacin administration caused dose-dependent damage and increased PMN margination and plasma TNF concentrations. Pretreatment with interleukin 2 and lipopolysaccharide significantly increased TNF release, PMN margination, and gastric mucosal damage, but administration of dexamethasone, pentoxifylline, and G-CSF provided almost total protection. The administration of G-CSF alone caused a significant increase in gastric PMN margination but protected against the indomethacin-induced gastropathy. Conclusions: Agents that regulate TNF synthesis and release influence gastric susceptibility to indomethacin by modulating PMN margination. G-CSF increased PMN infiltration but protected against the mucosal injury, suggesting that PMN margination alone is not sufficient to induce mucosal damage.